The present invention relates to novel compounds which bind to the integrin receptor xcex1vxcex23, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents.
Integrins are a group of cell surface glycoproteins which mediate cell adhesion and therefore are useful mediators of cell adhesion interactions which occur during various biological processes. Integrins are heterodimers composed of noncovalently linked xcex1 and xcex2 polypeptide subunits. Currently eleven different xcex1 subunits have been identified and six different xcex2 subunits have been identified. The various xcex1 subunits can combine with various xcex2 subunits to form distinct integrins.
The integrin identified as xcex1vxcex23 (also known as the vitronectin receptor) has been identified as an integrin which plays a role in various conditions or disease states including tumor metastasis, solid tumor growth (neoplasia), osteoporosis, Paget""s disease, humoral hypercalcemia of malignancy, angiogenesis, including tumor angiogenesis, retinopathy including macular degeneration, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis and smooth muscle cell migration (e.g. restenosis artherosclerosis). Additionally, it has been found that such agents would be useful as antivirals, antifungals and antimicrobials. Thus, compounds which selectively inhibit or antagonize xcex1vxcex23 would be beneficial for treating such conditions.
It has been shown that the xcex1vxcex23 integrin and other xcex1v containing integrins bind to a number of Arg-Gly-Asp (RGD) containing matrix macromolecules. Compounds containing the RGD sequence mimic extracellular matrix ligands so as to bind to cell surface receptors. However, it is also known that RGD peptides in general are non-selective for RGD dependent integrins. For example, most RGD peptides which bind to xcex1vxcex23 also bind to xcex1vxcex25, xcex1vxcex21 and xcex1IIbxcex23. Antagonism of platelet xcex1IIbxcex23 (also known as the fibrinogen receptor) is known to block platelet aggregation in humans. In order to avoid bleeding side-effects when treating the conditions or disease states associated with the integrin xcex1vxcex23, it would be beneficial to develop compounds which are selective antagonists of xcex1vxcex23 as opposed to xcex1IIbxcex23.
The compounds of this invention are therefore selective xcex1vxcex23 integrin antagonists. The present invention includes compounds which inhibit the respective integrin and also includes pharmaceutical compositions comprising such compounds. The present invention further provides for methods for treating or preventing conditions mediated by the xcex1vxcex23 receptor in a mammal in need of such treatment comprising administering a therapeutically effective amount of the compounds of the present invention and pharmaceutical compositions of the present invention. Administration of such compounds and compositions of the present invention inhibits angiogenesis, tumor metastasis, tumor growth, osteoporosis, Paget""s disease, humoral hypercalcemia of malignancy, retinopathy, macular degeneration, arthritis, periodontal disease, smooth muscle cell migration, including restenosis and artherosclerosis, and viral diseases.
Tumor cell invasion occurs by a three step process: 1) tumor cell attachment to extracellular matrix; 2) proteolytic dissolution of the matrix; and 3) movement of the cells through the dissolved barrier. This process can occur repeatedly and can result in metastases at sites distant from the original tumor.
Seftor et al. (Proc. Natl. Acad. Sci. U.S.A., Vol. 89 (1992) 1557-1561) have shown that the xcex1vxcex23 integrin has a biological function in melanoma cell invasion. Montgomery et al., (Proc. Natl. Acad. Sci. U.S.A., Vol. 91 (1994) 8856-60) have demonstrated that the integrin xcex1vxcex23 expressed on human melanoma cells promotes a survival signal, protecting the cells from apoptosis. Mediation of the tumor cell metastatic pathway by interference with the xcex1vxcex23 integrin cell adhesion receptor to impede tumor metastasis would be beneficial.
Brooks et al. (Cell, Vol. 79 (1994) 1157-1164) have demonstrated that antagonists of xcex1vxcex23 provide a therapeutic approach for the treatment of neoplasia (inhibition of solid tumor growth) since systemic administration of xcex1vxcex23 antagonists causes dramatic regression of various histologically distinct human tumors.
The adhesion receptor integrin xcex1vxcex23 was identified as a marker of angiogenic blood vessels in chick and man and therefore such receptor plays a critical role in angiogenesis or neovascularization. Angiogenesis is characterized by the invasion, migration and proliferation of smooth muscle and endothelial cells. Antagonists of xcex1vxcex23 inhibit this process by selectively promoting apoptosis of cells in neovasculature. The growth of new blood vessels, or angiogenesis, also contributes to pathological conditions such as diabetic retinopathy including macular degeneration (Adamis et al., Amer. J. Ophthal., Vol. 118, (1994) 445-450) and rheumatoid arthritis (Peacock et al., J. Exp. Med., Vol. 175, (1992), 1135-1138). Therefore, xcex1vxcex23 antagonists would be useful therapeutic agents for treating such conditions associated with neovascularization (Brooks et al., Science, Vol. 264, (1994), 569-571).
It has been reported that the cell surface receptor xcex1vxcex23 is the major integrin on osteoclasts responsible for attachment to bone. Osteoclasts cause bone resorption and when such bone resorbing activity exceeds bone forming activity it results in osteoporosis (loss of bone), which leads to an increased number of bone fractures, incapacitation and increased mortality. Antagonists of xcex1vxcex23 have been shown to be potent inhibitors of osteoclastic activity both in vitro [Sato et al., J. Cell. Biol., Vol. 111 (1990) 1713-1723] and in vivo [Fisher et al., Endocrinology, Vol. 132 (1993) 1411-1413]. Antagonism of xcex1vxcex23 leads to decreased bone resorption and therefore restores a normal balance of bone forming and resorbing activity. Thus it would be beneficial to provide antagonists of osteoclast xcex1vxcex23 which are effective inhibitors of bone resorption and therefore are useful in the treatment or prevention of osteoporosis.
The role of the xcex1vxcex23 integrin in smooth muscle cell migration also makes it a therapeutic target for prevention or inhibition of neointimal hyperplasia which is a leading cause of restenosis after vascular procedures (Choi et al., J. Vasc. Surg. Vol. 19(1) (1994) 125-34). Prevention or inhibition of neointimal hyperplasia by pharmaceutical agents to prevent or inhibit restenosis would be beneficial.
White (Current Biology, Vol. 3(9)(1993) 596-599) has reported that adenovirus uses xcex1vxcex23 for entering host cells. The integrin appears to be required for endocytosis of the virus particle and may be required for penetration of the viral genome into the host cell cytoplasm. Thus compounds which inhibit xcex1vxcex23 would find usefulness as antiviral agents.
The present invention as a first object provides compounds of the following formula (I) 
or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein
G is selected from the group consisting of: 
wherein Q is NH or O and Qxe2x80x2 is H, C1-C6 alkyl, phenyl, or phenyl-C1-C4-alkyl; 
wherein Rxe2x80x2 and Rxe2x80x3 are independently H or C1-C4 alkyl;
B is a C1-C4 alkyl or a C2-C4 alkenyl;
A is CH2, O, S(O)n wherein n is zero, 1 or 2, NH, a group CON(Rxe2x80x2xe2x80x3) or N(Rxe2x80x2xe2x80x3)CO wherein Rxe2x80x2xe2x80x3 is hydrogen or CH3;
R1 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 alkoxy, OH, halogen, and CF3;
X is Cxe2x95x90O or completes a single bond;
R2 is selected from the group consisting of H, C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4-alkylcycloalkyl; aryl unsubstituted or optionally substituted by one to three substituents independently selected from halogen, CF3, C1-C4 alkyl, hydroxy and C1-C4 alkoxy; aralkyl; and C5-C7 monocyclic heteroaryl ring containing one to three heteroatoms chosen from O, S, and N, unsubstituted or optionally substituted by one to three substituents independently selected from halogen, CF3, C1-C4 alkyl, hydroxy and C1-C4 alkoxy;
Y is (CH2)n wherein n is 1 or 2;
R is hydrogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, aryl or aryl-C1-C4 alkyl.
With the proviso that m can not be 0 when G is: 
wherein Qxe2x80x2 is H and Q is O and X is (Cxe2x95x90O)m.
The present invention includes within its scope all possible isomers, stereoisomers and optical isomers and their mixtures, and the bioprecursors or metabolites of the compounds of formula (I).
It is another object of the invention to provide pharmaceutical compositions comprising compounds of the Formula I. Such compounds and compositions are useful in selectively inhibiting or antagonizing the xcex1vxcex23 integrin and therefore in another embodiment the present invention relates to a method of selectively inhibiting or antagonizing the xcex1vxcex23 integrin. The invention further involves treating or inhibiting pathological conditions associated therewith such as osteoporosis, humoral hypercalcemia of malignancy, Paget""s disease, tumor metastasis, solid tumor growth (neoplasia), angiogenesis, including tumor angiogenesis, retinopathy including macular degeneration and diabetic retinopathy, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis, smooth muscle cell migration and restenosis in a mammal in need of such treatment. Additionally, such pharmaceutical agents are useful as antiviral agents, and antimicrobials.